JPH07110808B2 - Pharmaceutical composition - Google Patents

Description

Detailed Description of the Invention

The present invention relates mainly, but not exclusively, to the treatment of several diseases and disorders in the field of human medicine and to compositions for use therein. In recent years, there has been significant interest in using prostaglandin (PG) precursors in medicine.

For a variety of reasons, PGE1 and PGE2
It is not practical to administer a naturally occurring prostaglandin such as As a result, linoleic acid, γ
Significant attention has been focused on using prostaglandin precursors, including -linolenic acid (GLA) and dihomo-γ-linolenic acid (DGLA). It is believed that the transformation of these substances in vivo is as shown in the reaction equation of FIG.

Although the general outline of this pathway is well known, details on the regulation, inhibition and enhancement of this pathway can be found in
The inventor believes that it works as shown in FIG. This pathway will be discussed in particular with regard to the treatment of cancer and inflammation. This discussion is made due to the belief in describing the invention and is not intended to limit the invention to the content of the discussion believed to be the reason for the effectiveness of the invention.

The essential role of essential fatty acids (EFAs) is to act as a precursor of prostaglandins (PGs), and PGs series 1 is dihomo-γ.
-Formed from linolenic acid (DGLA), PGs series 2 is formed from arachidonic acid (AA). DG
LA and AA are only present in small amounts in food, and the major EFA in food is linoleic acid, which is first converted to γ-linolenic acid (GLA) and then to DGLA and AA. The conversion of linoleic acid to GLA is blocked by high-fat and high-carbohydrate foods, aging and obesity. Very large amounts of AA are stored in the body in the form of lipid esters. In contrast, DGLA is present in only small amounts.

There is evidence in cancer that there is excessive production of prostaglandins, abnormal calcium levels, and conversion of oxidative to glycolytic modes of metabolism. The inventor believes that they are due, in part, to the lack of TXA2 synthesis. Such a lack is caused, for example, by irradiation. Furthermore, it is believed that in vivo, TXA2 binds to chromosomes and thereby increases the resistance of chromosomes to mutagens.

Therefore, there are two mechanisms for carcinogenesis, firstly T
It is suggested that reduced XA2 levels and secondly involve contact with mutagens that lead to uncontrolled proliferation. Therefore, many of the problems with cancer are
First, it is believed to be due to lack of TXA2 synthesis and, second, to excess series 2 prostaglandins and lack of series 1 prostaglandins and essential fatty acids. Therefore, the present invention has, as one of the features, γ
-Series 1 by administering linolenic acid and / or another substance that enhances the production of series 1 PG
It tries to make up for the lack of PG.

[0007] As another characteristic, the production of TAX2 is directly restored, preferably together with the first characteristic. Furthermore, <br/> essential factor in certain inflammatory diseases is that which may be migration of calcium into cells, were recently discovered. This would damage the mitochondria and activate the destructive lysosomal enzyme. Thus, adjustment and further controls intracellular calcium immune response can be a significant factor in the treatment of various inflammatory diseases, clone (Crohn 's)'s disease For example, and other later-described diseases.

The inventor has discovered that colchicine is a substance that can enhance the elimination of calcium by cells and appears to be able to control intracellular calcium. Colchicine may also inhibit the formation of series 2 PG and enhance the formation of series 1 PG. Therefore, as one of the features of the present invention,
Colchicine is administered to control intracellular calcium with correction for EFA balance. The relationship between colchicine and EFA metabolism will be discussed later.

As discussed above, in cancer and in inflammatory diseases, arachidonic acid to series 2PG
The production of s is significantly enhanced. In inflammatory diseases,
Series 2 PGs are thought to be responsible for the disease. The reason is that both steroids and aspirin-like drugs are partially effective, but steroids block the conversion of AA esters to free AA, and aspirin-like drugs are intermediates in free AA intermediates in PG synthesis. It blocks the conversion to endoperoxide. Although there is little evidence that increased production of series 2 PGs plays an important role in cancer, some human tumors respond to steroids and the growth of some human tumors is blocked with aspirin-like drugs.

Overproduction of Series 2 PGs means loss of normal control of the PG synthesis pathway. Control of this pathway is not fully understood, but two factors have been identified. 1. PGE1 can inhibit the formation of free AA more than AA ester. This leads to the paradoxical fact that a partial lack of EFA actually leads to increased formation of Series 2 PGs. The reason for this is that the storage of DGLA is much less than that of AA, and the partial lack of EFAs therefore leads firstly to the lack of DGLA. This lack reduces PGE1 formation, leading to AA
Control of PGE1 is lost and allows the overproduction of Series 2 PGs over AA which is stored in large quantities.

2. The unstable product of AA metabolism, thromboxane A2 (TXA2), appears to block the conversion of AA ester to free AA, and possibly also the conversion of free AA to PG2 endoperoxide. Feed back. So loss of TXA2 would also lead to overproduction of Series 2 PGs. Thus, TXA2 and PGE1 cooperate to regulate the formation of series 2 PGs, leading to abnormalities if either formation is impaired.

[0012] So, for example, abnormal PG synthesis in inflammatory diseases and cancers can be caused by PGE1 and / or T
Inappropriate formation of XA2 may be explained. The above is a brief description of the evidence that PGs are directly involved in inflammatory diseases and cancer. In addition, there is also indirect evidence that prostaglandins act in a -or non-regulatory way to regulate the movement of calcium in and out of the cells described above. Calcium levels in the cytoplasm are usually very low, and a transient increase in calcium levels in the cytoplasm causes a variety of intracellular events, including activation of lysosomes that contain cell division and destructive enzymes. There is good evidence of many facts about being a pull. Usually, this calcium is removed very quickly after this transient activation, ending these phenomena. PGs and similar substances have a calcium-specific effect, and the inventor
Evidence was obtained suggesting that XA2 and PGF2α may have essential importance. In particular, specific inhibition of TXA2 synthesis significantly extends the time required for elimination of calcium from the cytoplasm after activation. Furthermore, when TXA2 synthesis is inhibited, PGF2α and PGE2, which can promote the translocation of calcium into cells,
Results in an increase in the formation of. In this context, there is good evidence that PGE1 and TXA2 reinforce each other's effects. Particularly in muscle, the degree of contraction is related to the calcium concentration in the cytoplasm, and muscle contraction is one measure of this calcium concentration. Inhibition of TXA2 synthesis greatly prolongs recovery from contraction, which indicates that
It means a slow loss of calcium. Furthermore, TXA
Inhibition of 2 synthesis can lead to a chronic condition of partial contraction, suggesting translocation of calcium into the cytoplasm. T
PGF2α and PGE2 are increased by inhibition of XA2 synthesis
Increased production of L also leads to contraction, suggesting translocation of calcium to the cytoplasm.

Decreased TXA2 and PGE1 synthesis will lead to increased formation of series 2 PGs and translocation of calcium to the cytoplasm. This calcium can activate cell division and, in addition, activate lysosomes, which produce destructive enzymes that can play a major role in inflammation. There is much evidence that cancer does not normally produce TXA2. The most notable is as follows. (A) Specific inhibitors of TXA2 synthesis, such as imidazole, can cause normal cells to undergo biochemical abnormalities similar to naturally occurring cancers. (B) Both radiation and phorbol esters, which strongly promote the development of cancer, can inhibit the enzyme that forms TXA2.

Evidence of a lack of series 1 PG synthesis in cancer is currently less substantive. However, rapidly growing cancers often cause skin disorders in the host, which is similar to that due to the lack of Series 1 PG. Moreover, for rat breast cancer,
There is evidence that the synthesis of α-lactalbumin is regulated by PGE1 and that when the breast tissue changes from a normal state to a cancerous state, the synthesis of α-lactalbumin ceases.

There is evidence to suggest that TXA2 can protect DNA from mutations. For example, phorbol esters do not cause mutations per se, but make cells significantly more susceptible to the action of other mutagens or, in particular, make cells more sensitive to the onset of mutagenic effects. It is possible that even in the case of the mutation itself, it may not be expressed in the presence of a suitable amount of TXA2. For example, exposure of a rat at birth to mutagenic radiation only when phorbol ester was administered
Cancer develops by the end of a year.

On a general basis, there is reason to expect that suppression of excessive production of Series 2 PGs will have desirable effects in both inflammatory diseases and cancer. The conventional method of suppression that can be used now is to administer steroids and aspirin-like drugs. But these are
It will suppress overproduction of Series 2 PGs, but will enhance it if there is a lack of Series 1 PGs and TXA2. Perhaps because of this, even if they suppress the symptoms, they usually do not change the long-term course of the disease.

The present invention controls the production of excess PG2 series to return to normal or series 1 PG
It provides a fundamentally new approach to enhance the production of either or both s and TXA2. The method for doing this is as follows. Increasing the useful supply of precursors of Series 1 PGs by supplying an appropriate amount of GLA or DGLA that bypasses any metabolic block between Series 1 PGs LA and GLA. GLA or DGLA can be synthetic or naturally occurring. Series 1 PGs can be further enhanced by administering the drug in combination with GLA or DGLA. A drug having this effect will be specifically shown later. Among these are penicilla-mine and levamisole, both of which have been used as anti-inflammatory agents in rheumatoid arthritis, but the mechanism is completely unknown. TXA2 PG2 series TXA using a drug that specifically activates an enzyme that produces TXA2 from endoperoxide
Enhances the production of 2. These drugs will also be specifically shown later. These include similar compounds such as colchicine and Vinca alkaloids.

These compounds, at high doses,
Much less than is currently used in the treatment of cancer is used, as it can have the opposite effect of inhibiting 2 production.
Colchicine and Vinca alkaloids present a seemingly contradictory situation in which they act on cancer in one of two ways. According to the invention, low doses inhibit the formation of other series 2 PGs and restore calcium regulation. Therefore, they tend to restore cancer cells to normal. However, at higher doses it appears to be toxic to the enzyme, as in known therapies. As a result, the remaining TXA2 synthetic ability is lost, and PG
It kills cells by enhancing the production of F2α and other series 2 PGs and increasing calcium translocation to toxic levels. However, this effect is not as selective as it is useful against cancer cells.

It may be noted that irradiation also seems to have contradictory effects, which are also explained in the concept underlying the present invention. Treatment of normal cells with sublethal irradiation inactivates TXA2 synthesis, leading to the abnormalities seen in cancer. Irradiation of cells that are already deficient in TXA2 phasing kills them by making them superfluous with calcium. This effect is then selective for cancer cells.

Direct evidence of efficacy in the treatment of cancer and inflammatory diseases is given later in this specification. Next,
It will be explained how γ-linolenic acid and similar substances were conventionally used in medicine, and then the present invention will be described in detail. Conventional Methods Conventional methods in this general area are included in the following patents and literature.

(I) John Williams, United States Patent Nos. 3933775 (patent of November 23, 1976) and 4058594 (19).
(November 15, 1977 announcement). This provides a method of providing an immunosuppressive effect to patients who have undergone organ or tissue transplants or who have multiple sclerosis. Here, 5 mg of γ-linolenic acid or dihomo-γ-linolenic acid or a functional derivative thereof
To 3 g daily.

(Ii) British Patent No. 1082625 published by Calmic on September 6, 1967. This is γ- in diseases of the vascular system.
It shows the effect of linolenic acid. (iii) Mc Corack, Neil and Sim's paper (The Lancet,
308, September 3, 1977). It describes a preliminary work on the use of oils containing linoleic acid and γ-linolenic acid as triglycerides in rheumatoid arthritis.

(Iv) Sim and Mc Craw's paper (Thrombosi
S Research, 10: 385-397, 1977). It describes the activity of methyl esters of γ-linolenic acid and dihomo-γ-linolenic acid in vitro- and in vivo on platelets in humans or non-human mammals. (v) Zurier and Quagliata's paper (Nature 234: 30
4, 1971). This describes the inhibitory effect of PGE1 on adjuvant arthritis in rats.

(Vi) Zurier, Sayadoff, Torrey and Rot
An article by hfield (Arthritis Rheum 20: 723, 1977). This is a human medical cause, lupus erythematosu.
s), which describes an inhibitory effect of PGE1 on naturally occurring inflammatory conditions in mice. The Invention With reference to the above general discussion, the above-cited prior art method and the present inventor's United States Patent Application No. 4924 dated Jan. 19, 1979, optionally with linoleic acid and, if desired, other fatty acids. In combination with γ-linolenic acid and
The invention is characterized by the use of (or) dihomo-γ-linolenic acid, which acids can be used with physiologically similar functional derivatives if desired. This can be written as A. (a) A substance that enhances the physiological synthesis of TXA2, or
(b) γ-linolenic acid or other substances as described above, in combination with both such substances and substances which selectively enhance the physiological synthesis of 1-series PGs, may be pharmaceutically acceptable. A pharmaceutical composition contained in a vehicle.

Compositions containing zinc and (or .gamma.-linolenic acid in combination with .beta.-lactam antibiotics, which are believed to provide 1-series PG enhancement, are particularly the subject of the above-referenced US patent applications. B. (a) Colchicine, vinblastine,
Vincristine (vincri-stine), griseofulvin (gr
iseofulvin) and other Vinca alkaloids, amatadine, melatonine (pineal hormone) or interferons, and optionally (b)
A pharmaceutical composition containing [gamma] -linolenic acid or another of the above substances in an acceptable pharmaceutical vehicle in combination with zinc, a [beta] -lactam antibiotic, penicillamine, phenformin or levamisole.

In particular, the composition for the treatment of cancer comprises (a) γ-linolenic acid and, optionally in combination with linoleic acid, optionally as a physiologically similar functional derivative. (Or) dihomo-γ-linolenic acid;
(b) An effective amount of a substance selected from the group consisting of zinc, penicillin and penicillamine; and (c) an effective amount of a substance selected from the group consisting of colchicine, vinblastine, vincristine, griseofulvin, interferon and amantadine can be used. .

[0027] The treated inflammatory disease can be, the internal cause of lupus erythematosus, clone (Crohn)'s disease, ulcerative colitis,
Inflammatory example Itokasa body nephritis kidney, nephrotic syndrome, nervous and muscular system inflammatory and degenerative diseases, for example muscular dystrophy, free Dora torquecontrol (Friedrei
ch) Similar pathologies with ataxia and alterations of peripheral nerves, autoimmune diseases, and other collagen diseases, rheumatoid arthritis, other inflammatory joint diseases, inflammatory skin diseases, familial Mediterranean fever
Deficiencies characterized by recurrent inflammation such as erranean Fever or Behcet's Syndrome are included.

If a composition containing the above-mentioned active substances is not desired, the above-mentioned substances can be administered separately or in suitable relative proportions, such that one part is combined and one part is administered separately. Packs containing may also be manufactured. Such packs are also within the scope of this invention. Although the present invention is primarily described as a pharmaceutical composition, γ-linolenic acid and other acids have the properties of food additives and may therefore be incorporated into edible margarine or other food products. Such foodstuffs probably contain other active substances and, here,
It is generally within the scope of the present invention as it is described as a food or pharmaceutical composition and is therefore included in the pharmaceutical composition in the claims.

The description of the invention as a human medicine can be applied to disease states in need of treatment in animals, so that the invention can also be applied in the field of veterinary medicine. The amounts of zinc and β-lactam antibiotics will be given in the general discussion below about these substances. The amounts of penicillamine, phenformin and levamisole, alternatives to zinc and lactam, are as follows:

Penicillamine 50 mg to 10 g / day Phenformin 10 mg to 5 g / day Levamisole 10 mg to 2 g / day In the present invention, a suitable dose of colchicine is 0.3 to 1.5 for inflammatory diseases, eg From 0.6 to 2.
4 mg colchicine / day. When other substances are used in combination with colchicine for inflammatory diseases, the amounts shown above may be used.

For cancer, the amount of colchicine, vinblastine, vincristine, griseofulvin, interferon or amantadine may conveniently be as follows. Colchicine 0.5 to 10 mg / day Amantadine 100 to 1000 mg / day Griseofulvin 0.5 to 5 g / day Vinblastine 0.5 to 5 mg / kg / week (average body weight 70 kg) Vincristine 0.1 to 1.0 mg / kg / week (average) Body weight 70 kg) Interferon (administered by injection) 1 × 10 ⁵ to 1 × 10 ⁸ units / day Melatonin 10 mg to 5 g / day The amounts of γ-linolenic acid and other acids are as follows.

For adults (weighing 75 kg), advantageous daily doses, both in the case of cancer and inflammatory diseases, range from 0.05 or 0.1 to 1, 2, 5 or 10 g as required. The amount of γ-linolenic acid is used, or in the case of a physiologically similar functional derivative of linolenic acid, the amount corresponding to linolenic acid is used. The amount may in particular be 0.1 to 1.0 g per day. This dose corresponds to a daily dose of about 2 to 20 g for Oenothera oil, discussed below. In place of or in addition to γ-linolenic acid, dihomo-γ-linolenic acid or a physiologically similar functional derivative thereof may be used, but its amount is also an amount corresponding to γ-linolenic acid in moles. . This dose may be administered, for example, once or, if convenient, may be given in 2, 3 or 4 divided doses.

According to the present invention, a particularly suitable daily dose for the treatment of cancer in adults (75 kg body weight) is 0.15 to 1.5.
g of γ-linolenic acid or equivalent functional derivative.
Also according to the present invention, a particularly suitable daily dose for an adult (75 kg body weight) inflammatory disease is an equivalent of 0.1 to 1.0 g of γ-linolenic acid or a functional derivative thereof.

The forms and materials of γ-linolenic acid and other acids are shown. γ-linolenic acid and dihomo-γ-
Convenient, physiologically identical functional derivatives of linolenic acid, according to the present invention, for all purposes mentioned above include C ₁ -C ₄ alkyl (eg methyl and ethyl) esters and glycerides. If you want
Natural or synthetic γ-linolenic acid (or physiologically functional derivative thereof) and / or dihomo-γ-linolenic acid
(Or a physiologically functional derivative thereof) itself may be combined with an acceptable pharmaceutical vehicle to produce a pharmaceutical composition for use in the present invention. For the time being, high γ
Γ in the form of an available oil with a linolenic acid content
Conveniently, linolenic acid is added to the composition.

At present, there are few natural oil raw materials known to have a high γ-linolenic acid content, and no natural raw material containing a significant amount of dihomo-γ-linolenic acid is known at all. . One source of oil currently available is
Oenothera biennis L. And the seeds of Evening Primrose, such as Oenothera lamarckiana . Extracted oils therefrom contain, in the form of glycerides, about 8% γ-linolenic acid and about 72% linoleic acid, based on the total fatty acid content, together with other glycerides. Other sources of γ-linolenic acid include Borago
Seeds of Borage species such as officinalis . Yield per acre is currently low, but Oenoth
It is a more abundant source of γ-linolenic acid than era oil. Recent studies on molds that can be cultivated by fermentation promise that the mold will be an oil feedstock.

The above-mentioned seed extract may be used as it is, or if desired, for example, fractionated to obtain γ-
An oily composition containing triglyceride of linolenic acid and linoleic acid as a main fatty acid component can be obtained. γ
If desired, linolenic acid can be included in large proportions. Seed extract oil appears to have a stabilizing effect on the dihomo-γ-linolenic acid or physiologically functional derivatives thereof contained therein.

Referring to the use of zinc, although not limited by theory, zinc promotes the biosynthesis of Series 1 PG, and specifically, the esterified and stored dihomo-γ-linolenic acid. It is peculiar in that it promotes the migration of the amount that is stored. This makes it possible to use zinc in combination with γ-linolenic acid and / or dihomo-γ-linolenic acid. The presence of any arachidonic acid or other substances that tend to counter this PG1 enhancing effect should of course be avoided.

In accordance with the present invention, a suitable daily dose of zinc for an adult (body weight 75 kg) is such that the amount of γ-linolenic acid, or other acid, or physiological equivalent is as discussed above. 2.5 to 800 mg, preferably 10
To 200 mg and preferably 10 to 80 mg. 10 to 80
mg zinc is about 0.125 to 1.0 mg / kg adult body weight. In view of the synergistic effect with zinc, the advantageous amount of γ-linolenic acid or other acid or physiological equivalent is smaller than in the absence of zinc, advantageously from a daily dose of 0.1
Set to 1.0 g. As mentioned above, this dose may be administered once, or may be divided into 2, 3 or 4 doses.

Zinc and γ-linolenic acid or other acids or derivatives are conveniently administered in combination in one preparation, but may be administered separately. Zinc should be administered in a form that is readily accessible in vivo. This usually indicates the use of zinc salts of inorganic or organic acids, which salts are physiologically tolerable at a given dose. Zinc salts, which are disturbing at higher doses, will also be sufficient for this purpose at the doses mentioned above.
Useful salts include zinc sulphate and zinc gluconate, and especially zinc oleate, γ-linolenate and dihomo-γ-linolenate. Zinc oxide may also be used. It is also possible to administer chelated zinc. In any case, the advantageous amounts of zinc are as described above. The amount is a calculated amount based on zinc metal.
Zinc oleate may be produced by the method described in Monatschrift 42 287 (1921). Similar methods can be applied, if desired, for the production of, for example, γ-zinc linolenate.

An experimental study on the use of zinc is described. In one group of experiments, the test preparation is the superior mesenteric artery bed isolated from male rats as described, for example, in Canadian J. Physiol Pharmacol 54: 357, 1976. The perfusion rate is a constant value of 3 to 4 ml / min, and the pressure is 25 to 30 mmHg. Na 150, K at nM 4.
Krebs bicarbonate buffer containing 3, Mg 1.0, Ca 2.5, phosphate 1.7, bicarbonate 25 and glucose 11.1 is used.

Prior to the test, 10 ng of the bitartrate form of norepinephrine is given intermittently, and the basal vasoconstrictor effect is measured as a transient increase in perfusion pressure for about 1 minute. Zinc chloride is added to the perfusion buffer in graded concentrations. The response to norepinephrine was measured 15 minutes after each.

The following results were obtained. Zinc concentration (μg / ml) response,% of basal level 0.1 112 0.2 0.2 118 0.4 130 0.8 138 50 μg / ml of indomethacin known to have inhibitory effect on PG synthesis Zinc had no effect on the response to norepinephrine when used in conjunction with 10 ng / ml PGF2, which should give apparently normal vascular reactivity.

In a similar test using dihomo-γ-linolenic acid and PGE1, basal with 2.8 × 10 ^-11 M PG, up to 130% for basal reaction, respectively, in the presence of 50 ng / ml of acid. Increased up to 150% for reaction. The results show that zinc gives a reaction similar to dihomo-γ-linolenic acid and PGE1. Furthermore, this reaction is
It blocks G synthesis and does not occur when PGE2 is fed. Thus, the conditions produced by γ-linolenic acid (and similarly effective dihomo-γ-linolenic acid) treatment are:
The addition of zinc appears to enhance the direction of Series 1 PG synthesis. Similar experiments with the same preparations show that phenformin, levamisole, penicillin and penicillamine show actions consistent with enhanced PGE1 synthesis.

The case where zinc is used in combination with other substances will be described. As noted above, zinc appears to increase PGE1 production from DGLA in the perfused mesenteric artery bed of rats. Colchicine (100ng / m2) in perfusate
l) or melatonin (10ng / ml) in the presence of PG
Increases the effect of zinc on E1 by a factor of 10 to 100. This effect varies with the one-year season and is greater in the summer than in the winter. This is probably because melatonin production from the pineal gland is lower in summer than in winter. So, the effect of adding melatonin is
It is easily found. Colchicine and melatonin are
It seems to act on the same site in the cell. And it seems that these effects overall increase PGE1 production. This effect is due, at least in part, to colchicine and melatonin thromboxane.
It is believed to be mediated by the effects on A2. The above-mentioned substances that replace colchicine are expected to have similar effects.

The use of β-lactam antibiotics will be described. The β-lactam antibiotics that can be used according to the present invention are conveniently known and include penicillins and cephalosporins including semi-synthetic ones, eg penicillin G, penicillin N, penicillin V. , Cephalexin, cephalothi
n), ampicillin, amoxicillin (am
oxycillin), cloxacillin and cephaloglycin. Any of these may be used as a non-toxic physiologically the same functional derivative, for example alkali metal salts, ie sodium and potassium salts, salts with organic bases. In this specification,
When referring to these antibiotics, such derivatives are also included.

A suitable daily dose will be 0.5 to 10.0 g daily for patients of average weight. This daily dose can be divided into divided doses as in the case of zinc. In long-term treatment, the use of penicillins is particularly desirable as it is known to have relatively few side effects. That is, penicillin has been used for many years to prevent Streptococcus infection in rheumatic heart disease, but has not been shown to be toxic with long-term administration.

Of course, it should be noted that the patient is not allergic to the selected drug. The reason these antibiotics are effective in certain diseases is believed to be because they enhance the utilization of what is stored as an ester of dihomo-γ-linolenic acid. For whatever reason, and without wishing to be bound by theory, zinc and antibiotics, when used with γ-linolenic acid or other acids and derivatives, are useful in the treatment of any of the conditions discussed herein. , Seems to show effects in the same direction.

Especially when tested in the rat mesenteric bed system described above, penicillin V and penicillin G
Gives a reaction similar to zinc in kind and degree, which means that β-lactam antibiotics behave similarly to zinc in all conditions treated according to the invention. Support the way of thinking. Colchicine enhances the effects of zinc, as well as
It can be expected to enhance the effects of antibiotics.

The drug formulation will be described. Compositions in accordance with the present invention include oral, rectal, in a suitable pharmaceutical vehicle, as discussed in detail in, for example, British Patent Specification No. 1082624 and are well known for each particular preparation. It is convenient to make the form suitable for injection or topical administration. It may be prepared, for example, in tablets, capsules, liquid or powder preparations for drinking, creams, lotions, or suppositories for topical application. Hydrolysis Oenot
An injectable solution of hera oil may be prepared using albumin to solubilize the free acid.

It is advantageous to add preservatives to the preparation. It has been found to be suitable for this purpose to use α-tocopherol at a concentration of about 0.1% by weight. Of course, in any given dosage unit, the absolute amount of active ingredient present should not exceed the dose rate and mode-suitable amount to be used, while a small number of doses achieves the desired dose rate. It is desirable that the amount be appropriate. The dosage rate will also vary depending on the precise drug effect desired.

The following are examples of therapeutically useful pharmaceutical compositions according to the present invention. Example Oenothera biennis L. Optionally extracted oil from seeds, methyldihomo-γ-linolenate and / or
Zinc sulfate and / or penicillin and / or
Combined with any of the other active agents described herein,
A pharmaceutical composition containing a unit dose is prepared by encapsulating a natural oil in soft gelatin capsules produced by known methods.

To extract oil from seeds, conventional methods such as cooling and pressurizing, screw pressurization after partially boiling seeds or solvent extraction are used. A representative sample of this oil contains 97.0% of the oil in the form of methyl ester, the relative proportions are: Palmitate 61.5 Stearate 1.6 Oleate 10.15 Linolenate 72.6 γ-Linolenate 8.9 α-Tocopherol as a preservative is added to the oil to a concentration of 0.1%.

A gelatin capsule containing the active ingredient was prepared by the conventional method using the extracted oil prepared as described above, wherein 0.5 g of the extracted oil contained about 0.045 g of γ-linolenic acid. Prepare by. Example 1 Extracted oil 0.5 g Zinc sulphate 10 mg In the treatment of cancer and inflammatory diseases as described above 1
Take 2 capsules 3 times daily. The daily dose of γ-linolenic acid will be about 0.27 g. Example 2 Extracted oil 0.5 g Dihomo-γ-methyl linolenate 10 mg Zinc sulphate 20 mg In the treatment of the above-mentioned cancers or inflammatory diseases, one day,
Take 2 capsules 3 times.

Example 3 Extracted oil 0.5 g Penicillin V 0.25 g In the above-mentioned cancer and inflammatory diseases, three capsules are administered per day to two capsules. Instead of penicillin, levamisole 25 mg, penicillamine 100 mg or phenformin 25 mg
Is used. Example 4 Extracted oil 0.5 g Penicillin V 0.25 g Zinc sulfate 10 mg In the above cancer or inflammatory disease, two capsules are administered three times a day. Instead of penicillin, levamisole 25 mg, penicillamine 100 mg, phenformin 25
mg is used.

Example 5 Extracted oil 0.5 g Methyldihomo-γ-linolenate 10 mg Penicillin V 0.25 g Zinc sulfate 10 mg In the above cancer or inflammatory disease, 3 capsules per day are administered .

Example 6 Extracted oil 0.5 g Zinc chloride 10 mg For the treatment of the above-mentioned cancers or inflammatory diseases, one capsule per day
Give 2 doses twice .

Example 7 Extracted oil cap with 70 mg / week of vinblastine
Cell or extract oil plus zinc capsules as in Example 1
Can be administered .

Example 8 Extracted oil cap with 70 mg / week of vincristine
Cell or extract oil plus zinc capsules as in Example 1
Can be administered .

Example 9 Extracted oil capsules combined with 0.5 g / day of melatonin
Or extract oil plus zinc capsules as in Example 1
You can .

Example 10 Extracted oil capsules or extracted oil plus zinc capsules may be administered as in Example 1 in combination with 1 × 10 ⁶ units / day of interferon.

Further examples of effects on inflammatory diseases are given. In inflammatory diseases in animals, PGE1 can improve the condition well (conventional methods (v) and (vi)). Thus agents that enhance the endogenous production of PGE1 are expected to have similar effects. Indeed, it is possible that penicillamine and levamisole are effective against rheumatoid arthritis, which is the first suggestion by the present inventor.

[Brief description of drawings]

FIG. 1 is a diagram showing a reaction process of essential fatty acids in vivo.

Claims (1)

[Claims] 1. A a series 1 prostaglandins / Series 2 pharmaceutical composition for use in the treatment of inflammatory diseases Ru caused by losing the balance of the prostaglandin, the composition γ- linolenic acid Alternatively, a pharmaceutical composition comprising a physiologically equivalent functional derivative and / or dihomo-γ-linolenic acid or a physiologically equivalent functional derivative, alone or in an acceptable pharmaceutical excipient.